Method of making solid dispersions of highly crystalline therapeutic compounds

ABSTRACT

A process for preparing solid dispersions of highly crystalline compounds. The highly crystalline or thermally labile therapeutic compounds are processed in an extruder in combination with a solubilizing agent and optionally a plasticizer. The resulting extrudate features the therapeutic compound in an amorphous state. Particularly useful as the solubilizing agents are surfactants such as poloxamers.

FIELD OF THE INVENTION

The present invention relates to a method of converting the physicalstate of a poorly water soluble therapeutic compound, for example, inorder to manufacture a solid dispersion. Specifically, the inventivemethod facilitates the change of a poorly soluble therapeutic compoundfrom a highly crystalline state into an amorphous state.

BACKGROUND OF THE INVENTION

Many poorly water soluble therapeutic compounds exist in a physicalstate that is highly crystalline. Additionally such high crystallinetherapeutic compounds often have high melting points. By converting thephysical state of such a therapeutic compound into an amorphous stateallows for both greater solubility and faster dissolution of thetherapeutic compound. This, thus, may increase the bioavailability ofthe drug.

Various methods have been used to achieve an amorphous state thatresults in the therapeutic compound being molecularly dispersed in aninert carrier, typically a polymer. Such methods include solventevaporation, spray drying, and melt fusion. Not all of these processesare ideal for converting the highly crystalline therapeutic compoundinto an amorphous state. Some methods may result in a product thatreverts back, or recrystallizes, into a crystalline state. Other methodsutilize organic solvents which may not be desirable due to environmentaland safety reasons.

Of particular interest is melt extrusion which uses a twin screwextruder to combine a therapeutic compound with an inert carrier to forma solid dispersion. Typically, the twin screw extruder is heated tofacilitate mixing of the therapeutic compound with the carrier.Sometimes heating a melt extruder to a temperature above the meltingpoint of a therapeutic compound may not be suitable since thattemperature could exceed the melting point of the carrier, thus causingthe carrier to decompose. Additionally, some therapeutic compounds maydecompose when melted.

Thus, there is a need for a process that allows for the use of meltextrusion to convert the physical state of a therapeutic compound frombeing highly crystalline to amorphous that is particularly appropriatefor therapeutic compounds that have either a high melting point and/oran attribute of decomposing near or at its melting point. This inventionaddresses such a need by utilizing a melt extrusion process thatincorporates a solubilizing agent. This solubilizing agent allows theprocessing temperature for a therapeutic compound to be lowered in orderto preserve the integrity of the therapeutic compound while allowing forthe physical state of the therapeutic compound to change fromcrystalline to amorphous. Furthermore, having such a process expands theformulation possibilities, as carriers or polymers that would normallydecompose at high temperatures may be subsequently used providinggreater flexibility for the pharmaceutical formulator.

SUMMARY OF THE INVENTION

Featured in the present invention is a method for making a soliddispersion which is particularly usefully for high melting point (i.e.,greater than or equal to 200° C.) therapeutic compounds and/ortherapeutic compounds that are thermally labile. The process comprisesthe steps of combining such a therapeutic compound with a carrier and asolubilizing agent to form a mixture; subsequently processing themixture in an extruder with heat, and extruding the mixture to form anextrudate. During processing in the melt extruder, the solubilizingagent facilitates the conversion of the physical state of thetherapeutic compound from being crystalline to amorphous, at a reducedprocessing temperature. This conversion to an amorphous state allows forthe formation of a solid dispersion that comprises the formerlycrystalline therapeutic compound.

In a further embodiment of the present invention, the process uses apoloxamer, especially poloxamer 188 as the solubilizing agent. The meltextruder is heated from a temperature of 50° C. to 175° C. or moreparticularly, 150° C. to 170° C.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate an exemplary embodiment of thepresent invention.

FIG. 1 depicts a chart showing two powder x-ray diffraction patterns ofa physical mixture of the exemplary constituents in Table 2 as comparedto a solid dispersion of the same constituents; and

FIG. 2. depicts a chart showing the respective powder x-ray diffractionpatterns for the individual constituents in Table 2 and the physicalmixture thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a melt extrusion process of making asolid dispersion of a high melting point, crystalline and/or thermallylabile poorly soluble therapeutic compound in an inert carrier with asolubilizing agent by using a melt extruder, for example a twin screwextruder. Particularly useful as the solubilizing agents are blockcopolymers, for example, non-ionic synthetic block copolymers ofethylene oxide and propylene oxide, i.e., poloxamer. Alternatively,solubilizing agents may also include other surfactants in addition tothe aforementioned class of block copolymers.

As used herein the term “pharmaceutical composition” means a mixturecontaining a therapeutic compound to be administered to a mammal, e.g.,a human, in order to prevent, treat or control a particular disease orcondition affecting the mammal.

As used herein the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions and/or dosage forms, which are,within the scope of sound medical judgment, suitable for contact withthe tissues of mammals, especially humans, without excessive toxicity,irritation, allergic response and other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein the term “therapeutic compound” means any compound,substance, drug, medicament, or active ingredient having a therapeuticor pharmacological effect, and which is suitable for administration to amammal, e.g., a human, in a composition that is particularly suitablefor oral administration.

As used herein the term “poorly soluble” refers to slightly soluble orvery slightly soluble as defined by the U.S. Pharmacopoeia, e.g., fromabout 100 to 10,000 parts of solvent required for one part of solute.

As used herein the term “crystalline” or “crystalline form” means havinga physical state that is a regular three-dimensional array of atoms,ions, molecules or molecular assemblies. Crystalline forms have latticearrays of building blocks called asymmetric units that are arrangedaccording to well-defined symmetries into unit cells that are repeatedin three-dimensions. In contrast, the term “amorphous” or “amorphousform” refers to an unorganized (no orderly) structure. The physicalstate of a therapeutic compound may be determined by exemplarytechniques such as x-ray diffraction, polarized light microscopy and/ordifferential scanning calorimetry.

As used herein the term “thermally labile” therapeutic compound refersto a therapeutic compound which undergoes spontaneous degradation ordecomposition when the therapeutic compound is heated at, above or nearits melting point.

As used herein, the term “high melting point” refers to a melting pointor the lowest point in a melting range that is greater than or equal to200° C.

Examples of therapeutic classes of therapeutic compounds include, butare not limited to, antacids, anti-inflammatory substances, coronarydilators, cerebral dilators, peripheral vasodilators, anti-infectives,psychotropics, antimanics, stimulants, antihistamines, anti-cancertherapeutic compounds, laxatives, decongestants, vitamins,gastrointestinal sedatives, antidiarrheal preparations, anti-anginaltherapeutic compounds, vasodilators, antiarrythmics, anti-hypertensivetherapeutic compounds, vasoconstrictors and migraine treatments,anticoagulants and antithrombotic therapeutic compounds, analgesics,anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants,anti-convulsants, neuromuscular therapeutic compounds, hyper- andhypoglycemic agents, thyroid and anti-thyroid preparations, diuretics,anti-spasmodics, uterine relaxants, mineral and nutritional additives,anti-obesity therapeutic compounds, anabolic therapeutic compounds,erythropoietic therapeutic compounds, anti-asthmatics, expectorants,cough suppressants, mucolytics, anti-uricemic therapeutic compounds, andtherapeutic compounds or substances acting locally in the mouth.

The therapeutic compound(s) is (are) present in the pharmaceuticalcompositions of the present invention in a therapeutically effectiveamount or concentration. Such a therapeutically effective amount orconcentration is known to one of ordinary skill in the art as the amountor concentration varies with the therapeutic compound being used and theindication which is being addressed. For example, in accordance with thepresent invention, the therapeutic compound may be present in an amountby weight of about 0.05% to about 99% weight of pharmaceuticalcomposition. In one embodiment, the therapeutic compound may be presentin an amount by weight of about 10% to about 95% by weight of thepharmaceutical composition.

As used herein the term “carrier” refers to a pharmaceuticallyacceptable matrix suitable for forming a solid or molecular dispersionof the therapeutic compound. Particularly useful as carriers arepolymers or mixtures of polymers. Types of polymers include, but are notlimited to, water-soluble, water-swellable, water insoluble polymers andcombinations of the foregoing.

Examples of polymers include, but are not limited to:

homopolymers and copolymers of N-vinyl lactams, e.g., homopolymers andcopolymers of N-vinyl pyrrolidone (e.g., polyvinylpyrrolidone),copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate;

cellulose esters and cellulose ethers (e.g., methylcellulose andethylcellulose) hydroxyalkylcelluloses (e.g., hydroxypropylcellulose),hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose),cellulose phthalates (e.g., cellulose acetate phthalate andhydroxylpropylmethylcellulose phthalate) and cellulose succinates (e.g.,hydroxypropylmethylcellulose succinate or hydroxypropylmethylcelluloseacetate succinate);

high molecular polyalkylene oxides such as polyethylene oxide andpolypropylene oxide and copolymers of ethylene oxide and propyleneoxide;

polyacrylates and polymethacrylates (e.g., methacrylic acid/ethylacrylate copolymers, methacrylic acid/methyl methacrylate copolymers,butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers,poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates));

polyacrylamides;

vinyl acetate polymers such as copolymers of vinyl acetate and crotonicacid, partially hydrolyzed polyvinyl acetate;

polyvinyl alcohol; and

oligo- and polysaccharides such as carrageenans, galactomannans andxanthan gum, or mixtures of one or more thereof.

Particular useful carriers are those with low glass transitiontemperatures (i.e., T_(g)). Examples of carriers with low glasstransition temperatures include but are not limited to PVP K30, PVP K17,and PVP/VA.

Along with the polymer, the carrier may contain other pharmaceuticallyacceptable ingredients, for example plasticizers.

As used herein, the term “plasticizer” refers to a material that may beincorporated into the pharmaceutical composition in order to decreasethe glass transition temperature and the melt viscosity of a polymer byincreasing the free volume between polymer chains. Plasticizers, forexample, include, but are not limited to, water; citrate esters (e.g.,triethylcitrate, triacetin); low molecular weight poly(alkylene oxides)(e.g., poly(ethylene glycols), poly(propylene glycols),poly(ethylene/propylene glycols)); glycerol, pentaerythritol, glycerolmonoacetate, diacetate or triacetate; propylene glycol; sodium diethylsulfosuccinate; and the therapeutic compound itself. The plasticizer canbe present in concentration from about 0% to 15%, e.g., 0.5% to 5% byweight of the pharmaceutical composition. Examples of plasticizers canalso be found in The Handbook of Pharmaceutical Additives, Ash et al.,Gower Publishing (2000).

As used herein, the term “solubilizer” refers to a material able tosolubilize or partially solubilize the therapeutic compound and/orpolymer. Particularly useful as solubilizers are surfactants. The term“surfactant” as used herein may include non-ionic surfactants, anionicsurfactants, and the like, and suitable combinations of two or morethereof.

Particularly useful as a solubilizer are water-soluble, non-ionicsynthetic block copolymers, such as polyoxyethylene-polyoxypropyleneblock copolymers. The generic term for such copolymers is poloxamer. Asused herein, the term “a poloxamer” refers to at least one polymerhaving the formula: HO(C₂H₄))_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H in which “a”and “b” denote the number of polyoxyethylene and polyoxypropylene units,respectively. Examples of poloxamers are shown in the following Table 1with their respective “a” and “b” values for inserting into theaforementioned formula:

TABLE 1 poloxamer 105 a = 11 b = 16 poloxamer 108 a = 46 b = 16poloxamer 122 a = 5 b = 21 poloxamer 123 a = 7 b = 21 poloxamer 124 a =11 b = 21 poloxamer 181 a = 3 b = 30 poloxamer 182 a = 8 b = 30poloxamer 183 a = 10 b = 30 poloxamer 184 a = 13 b = 30 poloxamer 185 a= 19 b = 30 poloxamer 188 a = 75 b = 30 poloxamer 212 a = 8 b = 35poloxamer 215 a = 24 b = 35 poloxamer 217 a = 52 b = 35 poloxamer 231 a= 16 b = 39 poloxamer 234 a = 22 b = 39 poloxamer 235 a = 27 b = 39poloxamer 237 a = 62 b = 39 poloxamer 238 a = 97 b = 39 poloxamer 282 a= 10 b = 47 poloxamer 284 a = 21 b = 47 poloxamer 288 a = 122 b = 47poloxamer 331 a = 7 b = 54 poloxamer 333 a = 20 b = 54 poloxamer 334 a =31 b = 54 poloxamer 335 a = 38 b = 54 poloxamer 338 a = 128 b = 54poloxamer 401 a = 6 b = 67 poloxamer 402 a = 13 b = 67 poloxamer 403 a =21 b = 67 poloxamer 407 a = 98 b = 67

An example of a particularly useful poloxamer is poloxamer 188 which iscommercially available as PLURONIC F68 from BASF (Mt. Olive, N.J.).

As used herein, the term “melt granulating” refers to an exemplaryprocess to form a molecular dispersion of the once highly crystallineand/or thermally labile therapeutic compound. The processing isaccomplished by the use of an extruder.

In general, an extruder includes a rotating screw(s) within a stationarybarrel with an optional die located at one end of the barrel. Along theentire length of the screw, distributive mixing of the materials (e.g.,the therapeutic compound, release retardant, and any other neededexcipients) is provided by the rotation of the screw(s) within thebarrel. Conceptually, the extruder can be divided into three sections: afeeding section; a heating section and a metering section. In thefeeding section, the raw materials are fed into the extruder, e.g. froma hopper. The raw materials can be directly added to the hopper withoutthe need of a solvent. In the heating section, the raw materials areheated to a particular temperature necessary for processing. Theprocessing temperature does not exceed the degradation temperature ofthe materials. For example, poloxamer 188 has a degradation temperatureof 175° C. The processing temperature can range from about 50° C. toabout 175° C., e.g., 150° C. to about 170° C. After the heating sectionis a metering section in which the mixed materials are optionallyextruded through a die into a particular shape. Types of extrudersparticularly useful in the present invention are single- and twin-screwextruders. Such equipment and techniques used to make pharmaceuticalcomposition by extrusion have been established and are well-known in theprior art. See, e.g., Jorg Breitenbach, Melt extrusion: from process todrug delivery technology, 54 EUR. J. OF PHARMACEUTICS ANDBIOPHARMACEUTICS 107-17 (2002) which is hereby incorporated by referencein its entirety. See also, e.g., U.S. Pat. Nos. 4,801,460; 5,456,923;5,700,410; and 5,945,127.

The manufacturing of the solid dispersions of the present inventionbegins with the compounding of the therapeutic compound along with thesolubilizer, optional plasticizer, and the carrier using melt extrusionto form an extrudate. The solubilizer, e.g., may be present in an amountfrom about 5% to about 40% by weight of the composition of theextrudate, e.g., from about 10% to about 35%, e.g., from about 25% toabout 30%. Similarly, the therapeutic compound, may be present in anamount from about 0.01% to about 50% by weight of the composition of theextrudate, e.g., from about 5% to about 40%, e.g., from about 10% toabout 20%. The heating and mixing of the therapeutic compound and thecarrier to form extrudate is accomplished by the use of an extruder. Thecarrier, e.g., can be present in an amount from about 1% to about 99% byweight of the composition. Unlike granules made during a wet granulationprocess, the melt extrusion process of the present invention does notrequire a granulation fluid, for example, water, methanol, ethanol,isopropanol or acetone during the granulation process.

The extrudate is, for example, subsequently milled into granules whichform the internal phase of the pharmaceutical composition. One ofordinary skill in the art will appreciate the necessary particle size ofthe granule that is necessary for the particular pharmaceuticalcomposition being formulated. For example, suitable particle sizes,include those of less than equal to 1,000 μm, 750 μm, 500 μm or 250 μm.Alternatively, the extrudate can be directly molded into tablets, cutinto multiparticles or processed into any other forms as known to one ofordinary skill in the art.

The resulting granules are, for example, particles of the therapeuticcompound embedded, substantially embedded in, coated, continuously ordiscontinuously, by the release retardant.

The resulting granules are, for example, particles of the therapeuticcompound coated or substantially coated by the granulation excipient, oralternatively, particles of the therapeutic compound embedded orsubstantially embedded with or within the granulation excipient.

Once the granules are obtained, the granules may be formulated into oralforms, e.g., solid oral dosage forms, such as tablets, pills, lozenges,caplets, capsules or sachets, by adding additional conventionalexcipients which comprise an external phase of the pharmaceuticalcomposition. The external phase of the pharmaceutical composition canalso comprise an additional therapeutic compound. Such solid oral dosageforms, e.g., are unit oral dosage forms. Examples of such excipientsinclude, but are not limited to, release retardants, plasticizers,disintegrants, binders, lubricants, glidants, stabilizers, fillers anddiluents. One of ordinary skill in the art may select one or more of theaforementioned excipients with respect to the particular desiredproperties of the solid oral dosage form by routine experimentation andwithout any undue burden. The amount of each excipient used may varywithin ranges conventional in the art. The following references whichare all hereby incorporated by reference discloses techniques andexcipients used to formulate oral dosage forms. See The Handbook ofPharmaceutical Excipients, 4^(th) edition, Rowe et al., Eds., AmericanPharmaceuticals Association (2003); and Remington: the Science andPractice of Pharmacy, 20^(th) edition, Gennaro, Ed., Lippincott Williams& Wilkins (2003).

Examples of pharmaceutically acceptable disintegrants include, but arenot limited to, starches; clays; celluloses; alginates; gums;cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone orcrospovidone, e.g., POLYPLASDONE XL from International SpecialtyProducts (Wayne, N.J.); cross-linked sodium carboxymethylcellulose orcroscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linkedcalcium carboxymethylcellulose; soy polysaccharides; and guar gum. Thedisintegrant may be present in an amount from about 0% to about 10% byweight of the composition. In one embodiment, the disintegrant ispresent in an amount from about 0.1% to about 1.5% by weight ofcomposition.

Examples of pharmaceutically acceptable binders include, but are notlimited to, starches; celluloses and derivatives thereof, for example,microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia,Pa.), hydroxypropyl cellulose hydroxylethyl cellulose andhydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp.(Midland, Mich.); sucrose; dextrose; corn syrup; polysaccharides; andgelatin. The binder may be present in an amount from about 0% to about50%, e.g., 10-40% by weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceuticallyacceptable glidants include, but are not limited to, colloidal silica,magnesium trisilicate, starches, talc, tribasic calcium phosphate,magnesium stearate, aluminum stearate, calcium stearate, magnesiumcarbonate, magnesium oxide, polyethylene glycol, powdered cellulose andmicrocrystalline cellulose. The lubricant may be present in an amountfrom about 0% to about 10% by weight of the composition. In oneembodiment, the lubricant may be present in an amount from about 0.1% toabout 1.5% by weight of composition. The glidant may be present in anamount from about 0.1% to about 10% by weight.

Examples of pharmaceutically acceptable fillers and pharmaceuticallyacceptable diluents include, but are not limited to, confectioner'ssugar, compressible sugar, dextrates, dextrin, dextrose, lactose,mannitol, microcrystalline cellulose, powdered cellulose, sorbitol,sucrose and talc. The filler and/or diluent, e.g., may be present in anamount from about 15% to about 40% by weight of the composition.

The mixture is heated to a temperature(s) less than the meltingtemperature of the therapeutic compound, and that of the solubilizer. Asthe mixture is being heated, it is also being kneaded by the screw(s) ofthe extruder. The mixture is maintained at the elevated temperature andblended for a time sufficient to form a granulated product. After themixture is conveyed down the entire length of the barrel, a granulatedproduct (being the extrudate) is obtained, and the granulated mixture iscooled.

After cooling, the extrudate can be milled and subsequently screenedthrough a sieve. The granules (which constitute the internal phase ofthe pharmaceutical composition) are then combined with solid oral dosageform excipients (the external phase of the pharmaceutical composition),i.e., fillers, binders, disintegrants, lubricants and etc. The combinedmixture may be further blended, e.g., through a V-blender, andsubsequently compressed or molded into a tablet, for example amonolithic tablet, or encapsulated by a capsule.

Once the tablets are obtained, they can be optionally coated with afunctional or non-functional coating as known in the art. Examples ofcoating techniques include, but are not limited to, sugar coating, filmcoating, microencapsulation and compression coating. Types of coatingsinclude, but are not limited to, enteric coatings, sustained releasecoatings, controlled-release coatings.

The utility of all the pharmaceutical compositions of the presentinvention may be observed in standard clinical tests in, for example,known indications of drug dosages giving therapeutically effective bloodlevels of the therapeutic compound; for example using dosages in therange of 2.5-250 mg of therapeutic compound per day for a 75 kg mammal,e.g., adult and in standard animal models.

The present invention provides a method of treatment of a subjectsuffering from a disease, condition or disorder treatable with atherapeutic compound comprising administering a therapeuticallyeffective amount of a pharmaceutical composition of the presentinvention to a subject in need of such treatment.

The following examples are illustrative, but do not serve to limit thescope of the invention described herein. The examples are meant only tosuggest a method of practicing the present invention.

An example of a poorly water soluble therapeutic compound appropriatefor the present invention is midostaurin which is a protein Kinase Cinhibitor. This crystalline compound has a high melting point of about260° C., and the compound decomposes upon melting. Furthermore, thecompound is light-sensitive and oxidizes.

TABLE 2 Ingredient Percentage (w/w) midostaurin 10% polyvinylpyrrolidone 40% poloxamer 188 40% Sorbitol 10% Total 100% 

The ingredients of Table 2 are weighed and placed into a mortar andpestle in which they are gently mixed for one minute forming a mixture.Subsequently the mixture is transferred to the feed section, or hopper,of a twin screw extruder. A suitable twin screw extruder is the HaakeMiniLab Micro Compounds Product #557-2200 available from Thermo ElectronCorp. (Waltham, Mass.). This extruder has a single zone has for mixing.The extruder is heated to a temperature of 150° C. The material travelsin the extruder with a residence time of about two minutes.

The resulting extrudate is semisolid with an approximate temperature of100°. To quickly solidify the extrudate, it is placed in a freezer.However, air-cooling can also be used to solidify the extrudate.Subsequently, the extrudate is milled and suitable for analyticaltesting.

FIG. 1 shows two powder x-ray diffraction patterns of a physical mixtureof the ingredients of Table 2 as compared to a solid dispersion producedby the inventive process of the present invention using the sameingredients. FIG. 2 provides a comparison in that the PXRD patterns ofthe individual ingredients are shown. FIG. 2 shows the physical mixture,midostaurin, plasticizer (i.e., sorbitol), solubilizer (i.e., poloxamer188), and carrier (i.e., polyvinyl pyrrolidone). In the solid dispersionpattern of FIG. 1, the midostaurin is amorphous since there are no sharkpeaks. Instead there is a halo which shows formation of the amorphoustherapeutic compound.

It is understood that while the present invention has been described inconjunction with the detailed description thereof that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the following claims. Otheraspects, advantages and modifications are within the scope of theclaims.

1. A method for making a solid dispersion comprising the steps of:combining a poorly soluble and crystalline therapeutic compound with acarrier and a solubilizing agent to form a mixture; processing saidmixture in an extruder while heating said mixture; and extruding saidmixture to form an extrudate, wherein said therapeutic compound in saidextrudate is amorphous.
 2. The method of claim 1, further comprising thestep of compressing said extrudate to form a solid oral dosage form. 3.The method of claim 1, wherein said solubilizing agent is a poloxamer.4. The method of claim 3, wherein said poloxamer is poloxamer
 188. 5.The method of claim 1, wherein said heating is from a temperature of 50°C. to 175° C.
 6. The method of claim 5, where said heating is from atemperature of 150° to 170° C.
 7. The method of claim 1, wherein saidsolubilizing agent is present in said mixture from about 10% to about40% by weight of the mixture.
 8. The method of claim 1, wherein saidmixture further comprises a plasticizer.
 9. The method of claim 1,wherein said plasticizer is sorbitol.
 10. The method of claim 1, whereinsaid therapeutic compound has a melting point equal or greater than 200°C.
 11. A method for making a solid dispersion comprising the steps of:combining a poorly soluble and thermally labile therapeutic compoundwith a carrier and a solubilizing agent to form a mixture; processingsaid mixture in an extruder while heating said mixture; and extrudingsaid mixture to form an extrudate, wherein said therapeutic compound insaid extrudate is amorphous.
 12. The method of claim 11, furthercomprising the step of compressing said extrudate to form a solid oraldosage form.
 13. The method of claim 11, wherein said solubilizing agentis a poloxamer.
 14. The method of claim 13, wherein said poloxamer ispoloxamer
 188. 15. The method of claim 11, wherein said heating is froma temperature of 50° C. to 175° C.
 16. The method of claim 15, whereinsaid heating is from a temperature of 150° C. to 170° C.
 17. The methodof claim 11, wherein said solubilizing agent is present in said mixturefrom about 10% to about 40% by weight of the mixture.
 18. The method ofclaim 11, wherein said mixture further comprises a plasticizer.
 19. Themethod of claim 18, wherein said plasticizer is sorbitol.
 20. A methodfor making a solid dispersion comprising the steps of: combiningmidostaurin with a carrier and a solubilizing agent to form a mixture;processing said mixture in an extruder while heating said mixture; andextruding said mixture to form an extrudate, wherein said midostaurin insaid extrudate is in an amorphous state.